Nine rare, disease-causing mutations of the gene, FBXL4, were found in nine affected children in seven families, including three siblings from the same family. An international team of researchers report the discovery in the American Journal of Human Genetics.

The lead author is Xiaowu Gai, PhD, director of the Center for Biomedical Informatics at Loyola University Chicago Stritch School of Medicine.

Mitochondrial diseases are caused by defects in mitochondria, the cell’s energy plants. Malfunctions in mitochondria lead to multi-systemic defects in the brain, heart, muscles, kidney and endocrine and respiratory systems. The many possible clinical symptoms include loss of motor control, muscle weakness, heart disease, diabetes, respiratory problems, seizures, vision and hearing problems, diabetes and developmental delays.

Mitochondrial diseases are caused by mutations in either mitochondrial DNA or in genes in the nucleus that encode for proteins that function in the mitochondria. Mitochondrial DNA is inherited from the mother. Thus, a child can inherit a mitochondrial disease either from the mother alone or from both parents carrying mutations in the same nuclear gene. Mitochondrial diseases affect between 1 in 4,000 and 1 in 5,000 people.

FBXL4 is a nuclear gene that encodes for a protein called F-Box and Leucine-Rich Repeat Protein 4. The study found that mutations of this gene lead to either truncated or altered forms of the protein. This results in cells having less mitochondrial DNA, decreased mitochondrial membrane potential and a faulty process in cell metabolism called oxidative phosphorylation. The study also proved that the FBXL4 protein is located exclusively in mitochondria, which was previously unrecognized.

While mutations in more than 100 genes have been linked to mitochondrial diseases, the new discovery adds another novel disease gene to the list. Consequently, genetic testing will enable more parents to discover the cause of their childrens’ mitochondrial diseases. “This knowledge will help give them the peace of mind that it was not something they did to cause the disease,” Gai said. More importantly, the discovery also will improve scientists’ understanding of mitochondrial diseases, and potentially lead to new drugs to treat the disorders, Gai said.

The discovery began with an 8-year-old girl who had a mitochondrial disease known as Leigh syndrome. She has been seen by Dr. Marni J. Falk of the Children’s Hospital of Philadelphia, who is a co-senior author of the study. A battery of genetic tests of the girl and her parents over the years all had failed to find any of the gene mutations previously known to cause mitochondrial diseases.

Gai and Falk used the high-performance computer cluster at Loyola’s Center for Biomedical Informatics to analyze billions of DNA sequences to identify the gene mutation in the child and her parents. The research team then reached out to other collaborators to see if any of their patients also had the FBXL4 mutation. Eight additional affected children in six unrelated families were found to also have disease-causing mutations in this gene.

The discovery is an example of how Loyola’s Center for Biomedical Informatics is using computational approaches to address basic biomedical questions. Isolating an unknown mutation can involve sequencing and analyzing a patient's entire genome, containing 6 billion base pairs (DNA letters). Powerful computational approaches and infrastructure are required to read and compare sequences of billions of DNA base pairs.

The study included collaborators from multiple research centers in the United States, Europe and the Middle East. In addition to Gai, the research team included co-first authors Daniele Ghezzi, Mark A. Johnson, Caroline A. Biagosch, Hanan E. Shamseldin and Tobias B. Haack and co-senior authors Peter Freisinger, Wolfgang Sperl, Holger Prokisch, Fowzan S. Alkuraya, Marni J. Falk and Massimo Zeviani.